Growth of skeletal and cardiac muscles, like that of dividing cells, is largely dependent on signaling through the Insulin/PI3K/Akt/FoxO pathway. Conversely, the atrophy of specific muscles upon disuse, wasting, or denervation and the systemic muscle wasting in fasting and disease states (e.g. cancer cachexia, sepsis, and untreated diabetes) results from reduced activity of this pathway. This rapid loss of muscle mass results primarily through accelerated degradation of myofibrillar and soluble proteins, but in most catabolic states (e.g. fasting), protein synthesis also decreases.
FoxO (forkhead box O) transcription factors, one of the main downstream mediators of PI3K (phosphatidylinositol-3 kinase)/Akt [also known as PKB (protein kinase B)] signal transduction pathway, play an important role in modulating cellular homoeostasis. Recent studies have revealed the significance of FoxO in bone, the interaction of FoxO with -catenin, along with mechanical stress-induced inactivation of FoxO via PI3K/Akt.
Development of these various types of atrophy requires the transcription of a common set of atrophy-related genes (“atrogenes”) by FoxO transcription factors, whose activation is sufficient to cause accelerated proteolysis and atrophy. In atrophying muscles, multiple components of the ubiquitin-proteasome pathway (UPS), such as the muscle-specific ubiquitin ligases, MuRF1 and Atrogin1/MAFbx, are induced and their induction is essential for rapid wasting. Another ubiquitin ligase that appears to be critical for atrophy is Trim32. Like MuRF1, Trim32 contains a tripartite motif (RING; B-box; coiled-coil), but also has six NHL repeats with putative protein binding properties, and mutations in the third repeat causes Limb Girdle Muscular Dystrophy 2H. We demonstrated that during muscle wasting, MuRF1 is essential for the ubiquitin-dependent degradation of proteins comprising the thick filament, while Trim32 catalyzes the linked disassembly and degradation of the desmin cytoskeleton, Z-band, and thin filament proteins, which are linked processes.